Viral pseudo-enzyme facilitates KSHV lytic replication via suppressing PFAS-mediated RTA deamidation

Yang Xu; Qiushi Zhang; Guoli Hou; Liang Hu; Tiaoyi Xiao; Xinyu Liang; Deliang Li; Junhua Li

doi:10.1016/j.virs.2025.04.005

June 2025

. doi: 10.1016/j.virs.2025.04.005

Citation: Yang Xu, Qiushi Zhang, Guoli Hou, Liang Hu, Tiaoyi Xiao, Xinyu Liang, Deliang Li, Junhua Li. Viral pseudo-enzyme facilitates KSHV lytic replication via suppressing PFAS-mediated RTA deamidation .VIROLOGICA SINICA, 2025, 40(3) : 340-348. http://dx.doi.org/10.1016/j.virs.2025.04.005

病毒假酶通过抑制PFAS介导的RTA脱酰胺化促进KSHV的裂解性复制

徐杨 ^a ,
张秋实 ^a ,
侯国力 ^a,b ,
胡亮 ^a ,
梁新宇 ^a ,
肖调义 ^a ,
李德亮 ^a,, ,
李军华 ^a,,

a 水产学院, 湖南农业大学;
b 感染与免疫科, 赫尔曼·奥斯特罗牙科学院, 南加利福尼亚大学

通讯作者： 李德亮, lidl@hunau.edu.cn; 李军华, lijunhua@hunau.edu.cn
收稿日期： 2024-11-16
录用日期： 2025-04-09

摘要

脱酰胺化是一种蛋白质翻译后修饰，通常被认为是蛋白质“老化”和功能衰减的标志。近年来，大量研究揭示脱酰胺化在调控生物过程和病毒感染中的关键作用。先前的研究表明，由磷酸核糖甲酰甘氨脒合酶 (phosphoribosylformylglycinamidine synthetase, PFAS) 介导的病毒复制和转录激活因子 (replication and transcription activator, RTA) 的脱酰胺化对于RTA的核易位和转录活性具有抑制作用。其中，RTA是致癌性的卡波西肉瘤疱疹病毒 (Kaposi’s sarcoma-associated herpesvirus, KSHV) 的主要调节因子。在此研究中，我们报告了谷氨酰胺氨基转移酶(viral glutamine amidotransferase, vGAT)被病毒利用，通过抑制RTA脱酰胺化促进KSHV的裂解性感染。具体而言，vGAT通过与RTA和PFAS相互作用抑制PFAS介导的RTA脱酰胺化，从而促进RTA核易位，抑制NF-κB信号激活的同时增强RTA介导的病毒ORFs (open reading frames) 的转录激活。值得注意的是，vGAT似乎对多个KSHV的ORFs兼具脱酰胺化作用。总之，这些发现揭示了病毒假酶被病毒利用通过调控脱酰胺化增强病毒感染。

Viral pseudo-enzyme facilitates KSHV lytic replication via suppressing PFAS-mediated RTA deamidation

Yang Xu ^a ,
Qiushi Zhang ^a ,
Guoli Hou ^a,b ,
Liang Hu ^a ,
Tiaoyi Xiao ^a ,
Xinyu Liang ^a ,
Deliang Li ^a,, ,
Junhua Li ^a,,

a. College of Fisheries, Hunan Agricultural University, Changsha, 410128, China;
b. Section of Infection and Immunity, Herman Ostrow School of Dentistry, University of Southern California, Los Angeles, CA 90089, USA

Corresponding author: Deliang Li, lidl@hunau.edu.cn Junhua Li, lijunhua@hunau.edu.cn
Received Date: 16 November 2024
Accepted Date: 09 April 2025

Abstract

Deamidation, a type of post-translational modification commonly considered a hallmark of protein “aging” and function decay, is increasingly recognized for its pivotal role in regulating biological processes and viral infection. Our previous study has demonstrated that the deamidation of replication and transcription activator (RTA), a master regulator of ubiquitous and oncogenic Kaposi's sarcoma-associated herpesvirus (KSHV), mediated by phosphoribosylformylglycinamidine synthetase (PFAS), hinders its nuclear import and transcriptional activity. Here we report that the viral glutamine amidotransferase (vGAT) pseudo-enzyme is exploited to facilitate KSHV lytic infection by inhibiting RTA deamidation. To be more specific, vGAT interacts with both RTA and cellular PFAS, and inhibits PFAS-mediated RTA deamidation, thus facilitating RTA nuclear localization and suppressing nuclear factor-kappa B (NF-κB) signaling activation, as well as augmenting RTA-mediated transcriptional activation of viral open reading frames (ORFs). In addition, vGAT appears to regulate the deamidation process of several viral ORFs of KSHV. Collectively, these findings unveil that a viral pseudo-enzyme is exploited to enhance viral infection via deamidation regulation.
- Kaposi's sarcoma-associated herpesvirus (KSHV)
- , viral glutamine amidotransferase (vGAT)
- , transcription activator (RTA)
- , Deamidation

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10.1016j.virs.2025.04.005-ESM.docx